Asthma is a chronic inflammatory disease of the lower respiratory tract characterized by airway hyperresponsiveness and mucus obstruction (Busse et al., Am J Respir Crit. Care Med 2004, 170:683-690). Bronchial asthma is the most common chronic disease affecting children and young adults and is a complex genetic disorder with several overlapping phenotypes (Cookson and Moffatt, Hum. Mol. Genet. 9: 2359-64 (2000); Weiss, Ann. Allergy Asthma Immunol., 87 (Suppl 1): 5-8 (2001)). There is strong evidence for a genetic component in asthma (Bleecker et al., Am J. Respir. Crit. Care. Med., 156: S113-6 (1997); Kauffmann et al., Chest, 121(3 Suppl): 27S (2002)). Multiple environmental factors are also known to modulate the clinical expression of asthma as well as the asthma-associated phenotypes: bronchial hyperresponsiveness, atropy and elevated IgE (Koppelman et al., Eur. Resp. J, 13: 2-4 (1999); Cookson, Nature, 25: B5-11 (1999); Holloway, Clin. Exp. Allergy, 29: 1023-1032 (1999)). It is a commonly held view that asthma is caused by multiple interacting genes, some having a protective effect and others contributing to the disease pathogenesis, with each gene having its own tendency to be influenced by the environment (Koppelman et al., 1999; Cookson, 1999; Holloway, et al., 1999). Thus, the complex nature of the asthma phenotype, together with substantial locus heterogeneity and environmental influence, has made it difficult to uncover factors that underlie asthma.
Pharmacologic analogues of cortisol (e.g. prednisone) have been used clinically since 1948 and remain the standard of care for the treatment of a variety of inflammatory diseases including asthma (Larj et al., Chest 2004; 126:138 S-149S). These glucocorticoids (GC) reduce pathological inflammation that is central to asthma, and they are thought to control clinical asthma symptoms through their anti-inflammatory effects (Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Summary Report 2007. J Allergy Clin Immunol 2007, 120:S94-138). For example, Martinez and co-workers report that inhaled fluticasone shows sustained (albeit reversible) improvement in the proportion of asthma episode-free days, a reflection of reduced inflammation, compared to placebo over a two-year study period (Guilbert et al., N Engl J Med 2006, 354:1985-1997). Curiously, anti-inflammatory agents that specifically target inflammatory cells (e.g. eosinophils, T and B cells) and their intercellular signaling pathways have not shown similar efficacy to GCs in human trials (Lemanske, Proc Am Thorac Soc 2009, 6:312-315). That argues against the idea that asthmatic inflammation is merely the result of interactions between external stimuli and classic inflammatory cells like eosinophils and T cells. Rather, it is likely to involve complex interactions among multiple cell types including non-inflammatory resident cells of the lung (i.e. airway epithelium, fibroblasts, and smooth muscle).
Therefore, there remains a need for a new model of asthma and the use of that model for diagnosis, drug screening, and treating asthma.